Submissions for variant NM_000443.4(ABCB4):c.1769G>A (p.Arg590Gln)

gnomAD frequency: 0.00625  dbSNP: rs45575636

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723739	SCV000226227	uncertain significance	not provided	2018-04-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000249752	SCV000304284	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000723739	SCV000490387	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Reported in association with ABCB4-related disorders in several individuals who were heterozygous for R590Q alone, homozygous for R590Q, or heterozygous for R590Q and another variant in the ABCB4 gene (Degiorgio et al., 2007; Ziol et al., 2008; Colombo et al., 2011; Poupon et al., 2013; Degiorgio et al., 2015; Lourebam et al., 2021; Almes et al., 2022; Nayagam et al., 2022; Vitale et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 22995991, 26324191, 18083082, 27825922, 31127640, 22675952, 25882097, 21119540, 23533021, 25807286, 28776642, 28924228, 28587926, 28765628, 27936482, 19584064, 29761167, 28733223, 31538484, 32893960, 17726488, Jarasvaraparn-2021[CaseReport], Lourembam-2021[CaseReport], 34662886, 35894240, 34942279, 35626323, 36982896, 18482588)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000662150	SCV000784493	uncertain significance	Progressive familial intrahepatic cholestasis type 3	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000014696	SCV000784494	uncertain significance	Cholestasis, intrahepatic, of pregnancy, 3	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000033067	SCV000784495	uncertain significance	Low phospholipid associated cholelithiasis	2018-03-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000987909	SCV001137402	uncertain significance	Progressive familial intrahepatic cholestasis type 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000014696	SCV001319987	benign	Cholestasis, intrahepatic, of pregnancy, 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000723739	SCV001962060	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	ABCB4: BS2
Invitae	RCV000723739	SCV002115634	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 590 of the ABCB4 protein (p.Arg590Gln). This variant is present in population databases (rs45575636, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of ABCB4-related conditions (PMID: 18482588, 21119540, 28733223, 31538484). ClinVar contains an entry for this variant (Variation ID: 13697). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000249752	SCV002548022	uncertain significance	not specified	2022-05-03	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.1769G>A (p.Arg590Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0045 in 251094 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is benign. c.1769G>A has been reported in the literature among individuals with ABCB4-related conditions such as Anicteric Cholestasis, low phospholipid-associated cholelithiasis (LPAC), Progressive familial intrahepatic cholestasis (example, Ziol_2008, Tuan Huynh_2019, Colombo_2011, Droge_2017). These data do not allow any conclusion about variant significance. At-least one co-occurrence in cis with another presumably pathogenic variant(s) has been reported (Colombo_2011, ABCB4 c.2284G>T, p.G762X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/Likely Benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000249752	SCV004025143	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000723739	SCV004224026	uncertain significance	not provided	2022-11-21	criteria provided, single submitter	clinical testing	BS1, BP2
OMIM	RCV000014696	SCV000034951	pathogenic	Cholestasis, intrahepatic, of pregnancy, 3	2009-10-01	no assertion criteria provided	literature only
OMIM	RCV000033067	SCV000056847	pathogenic	Low phospholipid associated cholelithiasis	2009-10-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000709935	SCV000840292	not provided	ABCB4-related disorders		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.